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This study aims to assess whether activation of primordial follicles through ovarian cortex fragmentation may increase the number of antral follicles present in the ovary of patients with diminished ovarian reserve. Secondary outcomes include number of oocytes retrieved and pregnancy rates after IVF.
Hypothesis; Evaluate whether the proposed intervention increases the pool of antral follicles (potentially stimulable ones).
Controlled, randomized, assessor-blind clinical trial.
Thirty-six patients of La Fe University Hospital (Valencia), previously confirmed as poor responders according to the European Society of Human Reproduction and Embryology (ESHRE) criteria, will be randomized to two treatment arms:
Subsequently the number of antral follicles in both intervention groups will be compared and also will be the number of antral follicles in the native ovary and the grafted one in each of the patients.
Patients will receive a standard IVF treatment for poor responders according to the protocols of the assisted reproduction unit of La Fe University Hospital.
The final aim is to assess the pregnancy rate in both groups, as well as parameters related to the reproduction technique when required.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control arm | No Intervention | No intervention is performed. Assessment of antral follicle count. IVF treatment. | |
| Experimental arm | Experimental | Perform intervention described: Laparoscopy. In vitro fragmentation of the ovarian tissue. Assessment of antral follicle count. IVF treatment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| In vitro fragmentation of the ovarian tissue | Procedure | Unilateral ovarian cortex extraction, in vitro fragmentation and reimplantation. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Metaphase II (MII) | Number of mature MII oocytes retrieved in the IVF cycles after triggering. | 36 hours after triggering |
| Measure | Description | Time Frame |
|---|---|---|
| Total Antral Follicle Count (AFC) - Initial Measure | AFC assessment was done on day 2-5 of the menstrual cycle. Ultrasound scan was performed using a GE iVoluson (General Electric, Spain) equipped with a 3D vaginal probe (6.5-9MHz). A bilateral two-dimensional scan was performed and the mean of the two largest diameters of each intra-ovarian avascular anechoic image was recorded. Antral follicles with a mean diameter from 2 to 10 mm were counted to establish AFC. Initial data refers to the measure taken before treatment. |
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Inclusion Criteria (must meet one):
Exclusion Criteria (must not meet any):
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| Name | Affiliation | Role |
|---|---|---|
| Cesar Diaz-Garcia, MD | La Fe University Hospital. University of Valencia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| La Fe University Hospital | Valencia | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35367015 | Derived | Diaz-Garcia C, Herraiz S, Pamplona L, Subira J, Soriano MJ, Simon C, Seli E, Pellicer A. Follicular activation in women previously diagnosed with poor ovarian response: a randomized, controlled trial. Fertil Steril. 2022 Apr;117(4):747-755. doi: 10.1016/j.fertnstert.2021.12.034. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Control Arm | No intervention is performed. Assessment of antral follicle count. IVF treatment. |
| FG001 | Experimental Arm | Perform intervention described: Laparoscopy. In vitro fragmentation of the ovarian tissue. Assessment of antral follicle count. IVF treatment. In vitro fragmentation of the ovarian tissue: Unilateral ovarian cortex extraction, in vitro fragmentation and reimplantation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Two participants in the control group and one in the surgery group were lost after assignment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Control Arm | No intervention is performed. Assessment of antral follicle count. IVF treatment. |
| BG001 | Experimental Arm | Perform intervention described: Laparoscopy. In vitro fragmentation of the ovarian tissue. Assessment of antral follicle count. IVF treatment. In vitro fragmentation of the ovarian tissue: Unilateral ovarian cortex extraction, in vitro fragmentation and reimplantation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Metaphase II (MII) | Number of mature MII oocytes retrieved in the IVF cycles after triggering. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Median | Inter-Quartile Range | Oocytes | 36 hours after triggering | Number of IVF cycles | Number of IVF cycles |
|
Day 1 (recruitment) up to final follow-up (6 months after recruitment)
No serious adverse events were registered. Just a postsurgical complication consisting of a 2-day fever episode was registered in 1 patient.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control Arm | No intervention is performed. Assessment of antral follicle count. IVF treatment. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Minor postsurgical complication | General disorders | Fever | Non-systematic Assessment | After surgery, 1 patient experienced a 2-day episode of fever of unknown origin. She was treated with paracetamol without requiring antibiotic treatment. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Cesar Diaz-Garcia | IIS La Fe | 961 24 67 00 | cesar.diaz@ivirma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 10, 2022 | Apr 11, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 10, 2022 | Apr 11, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D007246 | Infertility |
| ID | Term |
|---|---|
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
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| Baseline, day 2-5 of the menstrual cycle prior to treatment |
| Total Antral Follicle Count (AFC) - Final | AFC assessment was done on day 2-5 of the menstrual cycle and was followed for 6-month. To determine AFC, ultrasound scan was performed using a GE iVoluson (General Electric, Spain) equipped with a 3D vaginal probe (6.5-9MHz). A bilateral two-dimensional scan was performed and the mean of the two largest diameters of each intra-ovarian avascular anechoic image was recorded. Antral follicles with a mean diameter from 2 to 10 mm were counted to establish AFC. Final measure refers to the AFC count after ovarian fragmentation treatment. | Day 2-5 of the menstrual cycle 6 months after treatment |
| Initial Antimüllerian Hormone (AMH) Levels | AMH levels were determined on day 2-5 of the menstrual cycle to establish the initial baseline levels for each patient. A microparticle immunoassay kit integrated in the ABBOTT AxSYM® Plus system and software 5.20 (Abbott Laboratories, Abbot Park, IL, USA) was used to determine AMH levels prior treatment. | Baseline, day 2-5 of the menstrual cycle prior to treatment |
| Final AMH Levels | AMH levels were determined using a microparticle immunoassay kit integrated in the ABBOTT AxSYM® Plus system and software 5.20 (Abbott Laboratories, Abbot Park, IL, USA) 6 months after recruitment or basaline assessment. | Day 2-5 of the menstrual cycle 6 months after the treatment |
| Number of Cancelled IVF Cycles | Number of cancelled IVF cycles for low or no response to controlled ovarian stimulation. Cycles were cancelled because of a lack of an adequate follicular formation (one follicle of at least 17 mm) the day of triggering. | End of stimulation cycle (less than or equal to 30 days) |
| Fertilization Rate | All the mature oocytes retrieved were inseminated by intracytoplasmic sperm injection (ICSI). Percentage of successfully fertilized oocytes were registered 18 hours after oocyte insemination. | 18 hours after insemination |
| Number of Cycles With Embryo Transfer (ET) | One or 2 embryos were transferred on day 3 after egg collection. This outcome represents the number of cycles that culminate with embryo transfer. | On day 3 after egg collection |
| Number and Percentage of Cycles With Clinical Pregnancy | Clinical pregnancy was defined as the presence of a gestational sac and heart beat under ultrasonography | 6 weeks after embryo transfer |
| Live Birth Rate | Live birth rate was calculated by dividing the number of patients who achieved live birth in each cycle by the number of patients who initiated that cycle | 9 months or birth of one or more live babies |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Age, Continuous | Partner's age (years old) | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body Mass Index (BMI) | Body Mass Index (BMI) was calculated for all the recruited patients according to the formula kg/m^2. | Median | Inter-Quartile Range | kg/m^2 |
|
| Previous gestations | Count of Participants | Participants |
|
| Previous deliveries | Count of Participants | Participants |
|
| Previous miscarriages | Count of Participants | Participants |
|
| Infertility etiology | Count of Participants | Participants |
|
| Infertile duration | Mean | Inter-Quartile Range | months |
|
| Baseline Antral Follicle Count (AFC) | Median | Inter-Quartile Range | number of follicles |
|
| Baseline AMH | Mean | Inter-Quartile Range | ng/mL |
|
| Number of previous IVF cycles | Count of Participants | Participants |
|
Perform intervention described: Laparoscopy. In vitro fragmentation of the ovarian tissue.
Assessment of antral follicle count. IVF treatment.
In vitro fragmentation of the ovarian tissue: Unilateral ovarian cortex extraction, in vitro fragmentation and reimplantation.
|
|
|
| Secondary | Total Antral Follicle Count (AFC) - Initial Measure | AFC assessment was done on day 2-5 of the menstrual cycle. Ultrasound scan was performed using a GE iVoluson (General Electric, Spain) equipped with a 3D vaginal probe (6.5-9MHz). A bilateral two-dimensional scan was performed and the mean of the two largest diameters of each intra-ovarian avascular anechoic image was recorded. Antral follicles with a mean diameter from 2 to 10 mm were counted to establish AFC. Initial data refers to the measure taken before treatment. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Median | Inter-Quartile Range | Follicles | Baseline, day 2-5 of the menstrual cycle prior to treatment | Number of IVF cycles | Number of IVF cycles |
|
|
|
|
| Secondary | Total Antral Follicle Count (AFC) - Final | AFC assessment was done on day 2-5 of the menstrual cycle and was followed for 6-month. To determine AFC, ultrasound scan was performed using a GE iVoluson (General Electric, Spain) equipped with a 3D vaginal probe (6.5-9MHz). A bilateral two-dimensional scan was performed and the mean of the two largest diameters of each intra-ovarian avascular anechoic image was recorded. Antral follicles with a mean diameter from 2 to 10 mm were counted to establish AFC. Final measure refers to the AFC count after ovarian fragmentation treatment. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Mean | Inter-Quartile Range | Follicles | Day 2-5 of the menstrual cycle 6 months after treatment | Number of IVF cycles | Number of IVF cycles |
|
|
|
|
| Secondary | Initial Antimüllerian Hormone (AMH) Levels | AMH levels were determined on day 2-5 of the menstrual cycle to establish the initial baseline levels for each patient. A microparticle immunoassay kit integrated in the ABBOTT AxSYM® Plus system and software 5.20 (Abbott Laboratories, Abbot Park, IL, USA) was used to determine AMH levels prior treatment. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Median | Inter-Quartile Range | ng/mL | Baseline, day 2-5 of the menstrual cycle prior to treatment | Number of IVF cycles | Number of IVF cycles |
|
|
|
|
| Secondary | Final AMH Levels | AMH levels were determined using a microparticle immunoassay kit integrated in the ABBOTT AxSYM® Plus system and software 5.20 (Abbott Laboratories, Abbot Park, IL, USA) 6 months after recruitment or basaline assessment. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Median | Inter-Quartile Range | ng/mL | Day 2-5 of the menstrual cycle 6 months after the treatment | Number of IVF cycles | Number of IVF cycles |
|
|
|
|
| Secondary | Number of Cancelled IVF Cycles | Number of cancelled IVF cycles for low or no response to controlled ovarian stimulation. Cycles were cancelled because of a lack of an adequate follicular formation (one follicle of at least 17 mm) the day of triggering. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Number | Number of cycles | End of stimulation cycle (less than or equal to 30 days) | Number of IVF cycles | Number of IVF cycles |
|
|
|
|
| Secondary | Fertilization Rate | All the mature oocytes retrieved were inseminated by intracytoplasmic sperm injection (ICSI). Percentage of successfully fertilized oocytes were registered 18 hours after oocyte insemination. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Number | Percentage of fertilized oocytes | 18 hours after insemination | Number of mature oocytes | Number of mature oocytes |
|
|
|
|
| Secondary | Number of Cycles With Embryo Transfer (ET) | One or 2 embryos were transferred on day 3 after egg collection. This outcome represents the number of cycles that culminate with embryo transfer. | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Count of Units | Number of IVF cycles | On day 3 after egg collection | Number of IVF cycles | Number of IVF cycles |
|
|
|
|
| Secondary | Number and Percentage of Cycles With Clinical Pregnancy | Clinical pregnancy was defined as the presence of a gestational sac and heart beat under ultrasonography | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Count of Units | Number of IVF cycles | 6 weeks after embryo transfer | Number of IVF cycles | Number of IVF cycles |
|
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|
|
| Secondary | Live Birth Rate | Live birth rate was calculated by dividing the number of patients who achieved live birth in each cycle by the number of patients who initiated that cycle | Of the 18 patients in the initial control group, 2 dropped out of the study (one because she did not want to follow up and the other because she divorced her husband). Of the 16 patients in the experimental group, one patient left the study before treatment because she moved to another city. | Posted | Count of Participants | Participants | 9 months or birth of one or more live babies |
|
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| 0 |
| 16 |
| 0 |
| 16 |
| 0 |
| 16 |
| EG001 | Experimental Arm | Perform intervention described: Laparoscopy. In vitro fragmentation of the ovarian tissue. Assessment of antral follicle count. IVF treatment. In vitro fragmentation of the ovarian tissue: Unilateral ovarian cortex extraction, in vitro fragmentation and reimplantation. | 0 | 15 | 0 | 15 | 1 | 15 |
|
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